Cellular Mechanisms of Antidepressant Drug Actions in Neuropathic Pain Models

描述(申请人提供)：本项目将阐明抗抑郁药物对神经病理性疼痛的感觉和情感脑回路中信号转导的影响。神经性疼痛是一种慢性疾病，其特征是感觉障碍(机械和冷痛、热痛觉过敏)和情绪障碍(焦虑和抑郁)。大多数用于治疗这种疾病的痛样症状的药物疗效低，有严重的副作用，在阿片类药物的情况下，可能会导致虚弱的身体成瘾。因此，迫切需要开发更有效和更好的耐受性的药物来治疗慢性神经性疼痛。三环类抗抑郁药和选择性的5-羟色胺/去甲肾上腺素再摄取抑制剂同时具有抗痛觉过敏和抗抑郁特性。然而，长期使用它们也伴随着严重的不良反应。了解介导TCAs和SNRIs作用的细胞机制将有助于开发治疗神经病理性疼痛的新的、更有效的药物。我们实验室的初步研究表明，纹状体的一种强有力的调节剂RGS9-2 GPCR信号的幅度和脱敏，在TCAs的抗痛觉过敏和抗抑郁作用中起着强有力的调节作用。我们将使用遗传小鼠模型和基因转移方法来验证我们的假设，即NAC中的RGS9-2在神经病理性疼痛模型中负向调节TCA和SNRI的作用。此外，我们将使用生化和分子生物学方法来验证我们的假设，即调控TCA和SNRI效应的关键RGS9-2蛋白质-蛋白质相互作用，以及RGS9-2下游响应TCA和SNRI处理的长期表观遗传变化。最后，我们将在神经病理性疼痛模型中使用RNA测序来表征抗抑郁剂诱导的和RGS9-2调节的全局基因调控。我们的发现将阐明NAC中的GPCR信号机制调节抗抑郁药物对神经病理性疼痛的感觉和情感症状的影响的机制。

DESCRIPTION (provided by applicant): This project will elucidate antidepressant-induced changes on signal transduction in sensory and affective brain circuitry mediating neuropathic pain. Neuropathic pain is a chronic condition characterized by both sensory deficits (mechanical and cold allodynia, thermal hyperalgesia) and mood disorders (anxiety and depression). Most drugs used to treat the pain-like symptoms of this disorder have low efficacy, carry major side-effects and in the case of opioids may lead to debilitating physical addiction. Thus, there is a pressing need for the development of more efficacious and better tolerated medications for treating chronic neuropathic pain. Tricyclic antidepressants and the selective, serotonin/norepinephrine reuptake inhibitors contain both antiallodynic and antidepressant properties. However, their chronic use is also accompanied by severe adverse effects. Understanding the cellular mechanisms mediating the actions of TCAs and SNRIs will facilitate the development of novel and more efficacious medications for the treatment of neuropathic pain. Preliminary findings from our laboratory indicate that RGS9-2, a potent regulator of striatal GPCR signaling amplitude and desensitization, plays a potent, modulatory role in the antiallodynic and antidepressant actions of TCAs. We will use genetic mouse models and gene transfer approaches to test our hypothesis that RGS9-2 in the NAc negatively regulates the actions of TCAs and SNRIs in neuropathic pain models. In addition, we will use biochemical and molecular biological approaches to test our hypotheses on both the critical RGS9-2 protein-protein interactions modulating the effects of TCA and SNRI and the long-term epigenetic changes downstream of RGS9-2 in response to TCA and SNRI treatment. Finally, we will characterize antidepressant-induced and RGS9-2 modulated global gene regulation using RNA-sequencing in models of neuropathic pain. Our findings will clarify the mechanism by which GPCR signaling machinery in NAc modulates the effects of antidepressant drugs on the sensory and affective symptoms of neuropathic pain.